In this grant application, we propose to further advance the development of a pan-dengue antibody for potential use in passive immunization and therapeutic strategies. Dengue is the most important world-wide mosquito-borne viral disease, with over half of the world's population at risk for infection. Dengue is caused by four genetically related but serologically distinct viruses termed DV-1 to DV-4 that are members of the flavivirus genus. Recent estimates suggest that over 390 million infections occur per year, of which 96 million manifest clinical diseases. The high morbidity associated with dengue virus infection leads to significant public health, social, and economic impact on populations and countries where DVs are endemic. Dengue has been described as an emerging disease, with an increasing number of cases, disease severity, and geographical spread of the disease. There are currently no specific agents for the prevention or treatment of dengue, and several vaccine candidates are in development for dengue though none that are approved. Given the global health impact and expanding nature of dengue as well as a lack of specific agents to prevent or treat the disease, a potent therapeutic that targets all DVs would provide significant benefit towards meeting the large unmet clinical need for dengue. To this end, we have engineered, through computational chemistry and structural informatics, the antibody 4E5A, which efficiently binds and potently neutralizes DV1-4 and confers significant in vivo activity. The antibody targets an epitope on domain III of the E protei that is highly accessible on the virion and that is constrained in its ability to mutate. Given the attributes of 4E5A, we propose to further characterize and develop the antibody to Phase I clinical trials. Our studies will be aimed at (1) examining the safety and activity of 4E5A through a series of mechanistic in vitro studies and safety and efficacy in animal models of dengue, and (2) utilizing our structure-based network and protein engineering approach to probe structure (epitope)-activity and to identify additional backup candidates. Overall, 4E5A and related molecules will be used to test the clinical hypothesis that reducing viral titer through administration of an antibody will (a) reduce symptoms and (b) lessen or eliminate hemorrhagic complications associated with disease progression.